In the United States alone cancer is responsible for more than half a million deaths each year, and during this same period more than a million new cases will be diagnosed. Despite an intensive research effort, the development of new forms of therapy, and the expenditure of billions of dollars, the age-adjusted mortality has not changed over the past 40 years. Recently, new molecular targets are being exploited in an attempt to improve upon current methods of cancer treatment in the hope that this approach will lead to new agents that are universally applicable to a wide spectrum of cancers. Described in this proposal is a drug discovery program that seeks to identify agents that inhibit telomerase: an enzyme that plays a key role in cell immortalization. While most normal somatic cells do not express telomerase, enzyme activity has been detected in nearly all tumor cell lines and tissues. As the expression of telomerase appears to be an inherent feature of the malignant phenotype, it is postulated that inhibition of this enzyme will lead to the re-mortalization of cancer cells. As the cancer cells continue to divide, their telomeres will shorten, the cell will enter crisis, and die. Furthermore, because most normal somatic cells lack telomerase activity, mechanistic toxicity should be virtually nonexistent. The specific aims of this NCDDG Grant will be to discover and develop a telomerase inhibitor for the treatment of cancer. Specifically, the NCDDG will continue to expand its library consisting of 45,000 synthetic organic compounds. These compounds will be evaluated in an automated high throughput screen that currently has the capacity to test up to 3,000 compounds per day. As telomerase inhibition therapy represents a new paradigm in cancer therapeutics, it will be necessary to characterize telomere length and the expression of telomerase activity in a spectrum of human tumors in anticipation of the selection of model systems and clinical targets. The specificity of active compounds will be examined by testing active compounds against a panel of cellular enzymes. Optimization of the activity of compounds with an acceptable profile will be accomplished through the application of medicinal chemistry and the development of focused compound libraries that will be developed using combinatorial chemistry techniques. Compounds will then be tested for activity against a selected panel of tumor cell lines and normal somatic cells. A method of synthesis will be developed to produce sufficient compound for evaluation in animal models. Pharmacology, drug metabolism, and pharmacokinetic studies will be conducted to optimize the bioavailability and activity of the compound. Lead compounds will be evaluated against target cancers using human tumor xenografts derived from well-characterized cell lines, cells with demonstrated drug resistance, and transplantable human tumors. Based on the results of these studies, a candidate compound will be selected for preclinical development in anticipation of filing an IND and ultimately evaluation in clinical trials.